Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidepressants, other antidepressants,
ATC code: N06AX17

Milnacipran is a dual inhibitor of (5-HT) serotonin and noradrenaline (NA) re-uptake.
Unlike most tricyclic antidepressants, milnacipran has no affinity for α1-adrenergic or H1- histaminergic receptors.

Binding experiments suggest that milnacipran has no significant affinity for cholinergic (muscarinic) receptors.
Furthermore, milnacipran also has no affinity for dopamine D1 and D2, benzodiazepine and opioid receptors.

In humans:
• At therapeutic dose, plasma concentrations are constantly located at levels corresponding to a 50 to 90% inhibition of norepinephrine and serotonin re-uptake.
• The pharmacological effects observed in the gastro-intestinal and genito-urinary system appear to be related to inhibition of norepinephrine re-uptake which can exert an antagonistic effect on acetylcholine (indirect anticholinergic effect); • Milnacipran does not induce any clinically significant change in cardiac repolarization or conduction;
• It does not affect cognitive function and has little sedative effect; • Sleep disturbances improve in depressed patients treated with milnacipran. The latency time to fall asleep is reduced and also the number of night awakenings and the latency for onset of paradoxal sleep is increased. Total duration of sleep is increased.

The efficacy of milnacipran has been compared to that of tricyclic antidepressants and SSRI and has found to be less than that of clomipramine.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Milnacipran is well absorbed following oral administration. Bioavailability is about 85%. It is not affected by food.
The peak plasma concentration (Cmax) is reached approximately 2 hours (Tmax) after oral administration. This concentration is about 120 ng/ml after a single 50 mg dose. Concentrations increase proportionally with doses up to 200 mg per administration.
After repeated doses, steady state is reached within 2 to 3 days, with an increase in concentrations of around 70% to 100% compared to a single dose (Cmax = 216 ng/ml). Inter-individual variability is low.

Distribution
Protein binding is low (13%) and not saturable.
The distribution volume of milnacipran is around 5 l/kg with a total clearance of approximately 40 l/hr.


Renal and non-renal clearances are equivalent.
Biotransformation
Milnacipran is metabolized mainly by glucuronic acid conjugation.
Active metabolites have been found at very low levels without clinical relevance.


Elimination
Plasma elimination half-life is approximately 8 hours.
Elimination occurs mainly via the kidney (90% of the administered dose) with tubular secretion of the product in unchanged form.
After repeated doses, milnacipran is totally eliminated two to three days after termination of therapy.

High risk patients
Patients with impaired liver function
Hepatic impairment does not significantly affect the pharmacokinetics of milnacipran.

Patients with renal failure
In case of renal failure, milnacipran is eliminated more slowly, in proportion to the degree of renal function alteration (see section 4.2).

Patients aged over 65
Milnacipran’s pharmacokinetic parameters are not significantly altered in the elderly. However, physiological alteration of renal function should be taken into account (see section 4.2).